1. Field of the Invention
This invention concerns an in situ biodegradable hydrogel drug delivery system in which the components are assembled in a manner that provides a mechanism for the timed cleavage of a particular amide bond in a covalently linked active agent, leading to release of that agent, or of a particular amide bond in the hydrogel matrix, leading to the degradation of the hydrogel itself. The present invention utilizes timed bond degradation resulting in hydrogel degradation and/or release of an active agent from the hydrogel. Two mechanisms of agent loading for the hydrogel include: (i) passive entrapment; and (ii) covalent attachment. The present invention incorporates novel hydrogel chemistry enabling a time based biodegradation mechanism for the hydrogel. Thus, after an active agent has been released from the hydrogel, the hydrogel will be degraded via this biodegradation mechanism into smaller, soluble PEG conjugates, which are naturally cleared from the body (renal, hepatic, and so on) without resorting to surgical or other invasive procedures. Although not intended to limit the invention, the hydrogels in the present invention could be preferably used for following: (i) subcutaneous delivery of active agents into the body; and (ii) local intraductal delivery of active agents to the breast ducts for the treatment and image-guided interventions in ductal carcinoma in situ (DCIS).
2. Description of the Related Art
Hydrogels are cross-linked network of hydrophilic polymers with ability to absorb large amount of water and swell, while maintaining their three-dimensional structure. The molecules of different sizes can diffuse into and out of this swollen three-dimensional network, which allows their possible use as drug-depot for controlled release applications. Hydrogels show minimum tendency to adsorb protein from body fluids due to their low interfacial tension and they also resemble closely to the living tissue due to their high-water content, and soft and rubbery characteristics. Due to their above-mentioned properties, hydrogels find use as scaffolds in tissue engineering and drug delivery systems in various biomedical and pharmaceutical applications1,2. Most hydrogel-based drug delivery systems are implants designed to release drug locally at a predetermined rate.
Hydrogels are prepared by intermolecular crosslinking of polymer chains through multifunctional crosslinkers. Amongst the different polymers available, the poly(ethylene glycol) or PEG polymers are probably the most versatile polymers for medical applications because they possess chemically inert polyether backbone and show excellent solubility in aqueous media. PEG's are nontoxic, non-immunogenic, and non-biodegradable, which makes them suitable for modification with biologically active compounds3. Several PEG hydrogels have been prepared using different crosslinking mechanisms for drug delivery applications4-10. Unfortunately, the hydrogels when prepared using non-degradable chemical bonds are not cleared from the body unless removed by surgical or other invasive means, which is inconvenient at best. Therefore, biodegradation (chemical or enzymatic cleavage in physiological environment) has become an important criterion for hydrogel drug delivery systems as it ensures that the drug depot is naturally removed from the body by utilizing the existing clearing mechanisms (renal, hepatic, and so on), one the drug delivery objectives have been achieved.
Different degradable or cleavable chemical linkages have been used for conjugating the active agents to PEG's or other polymeric carriers, which includes: (i) autodegradable esters bonds; (ii) acid sensitive linkages like acetals, imines (Schiff bases), cis-aconityls, and hydrazones; (iii) reducible bond like disulfides; and (iv) enzyme-degradable peptide spacers11. The polymer such as poly-glutamate (PGA) has been used for conjugation with paclitaxel through degradable ester bond linked to the α-carboxylic moiety of PGA12. Henne et al. have synthesized novel folate peptide camptothecin conjugate to release free CPT under reduced conditions using releasable disulfide carbonate linker capable of conferring water solubility to the conjugate13. Furthermore, polymer-doxorubicin (“Dox”), conjugates with Schiff base linkages, which release Dox when exposed to acidic conditions, have been obtained11. HPMA-Gly-Phe-Leu-Gly-Dox conjugate has been developed in which the in-built tetrapeptidyl linker (Gly-Phe-Leu-Gly) is cleaved by cathepsin B enzyme to release the free dox14.
Degradable or cleavable bonds like esters, phosphate ester, anhydrides, imine, acetal, and ketal have been incorporated into the hydrogel matrix to obtain biodegradable hydrogel drug delivery systems15. Harris and Zhao4 reported the preparation of degradable hydrogels using, degradable ester bonds. They developed amine-reactive bifunctional PEG crosslinkers containing degradable ester bonds with in the crosslinker structure. They used these crosslinkers for intermolecular crosslinking of branched PEG amines to obtain degradable hydrogels and also showed the covalent attachment of protein to the hydrogel matrix through ester bonds. The release of the protein from the hydrogel was controlled by hydrolysis of ester bonds between the protein (active agent) and the hyrogel matrix (drug depot). Andac et al.16 prepared biodegradable hydrogels using disulfide-linked components, which could be cleaved with reducing agents. The PEG hydrogels have been degraded naturally by enzymes,17. Enzymatically degradable hydrogels containing passively entrapped (no covalent bond between the active agent and the carrier) have also been obtained18. Another variant known is the polymer drug conjugate covalently linked to the hydrogel matrix through an enzyme cleavable linker19. Saito and Hoffman11 developed polymer-dox conjugates, which could be covalently linked to biodegradable PEG hydrogels using acid cleavable Schiff base linkages.
However, polymeric carriers or hydrogel drug delivery systems developed, using the existing degradation technology do not exhibit timed degradation of the hydrogel matrix or the release of active agents. The present invention aims to fill this existing technology gap by developing PEG hydrogel technology, where the hydrogel biodegradations and the release of active agents from the hydrogel are timed, (“controlled”).